Hemorrhage is the most common cause of death among injured or treated individuals including those who die prior to reaching care, who die in emergency medical care, e.g. emergency room, or who die in the operating room (Holcomb 1997; Holcomb 1999). The most common causes of death of individuals in post-operative critical care are those involving sequellae of poorly controlled hemorrhage and shock. In the prehospital setting, most internal bleeding is not accessible for direct intervention. In the hospital setting, there are sources of bleeding which cannot be immediately controlled with the best surgical techniques, e.g. deep liver injuries with liver vein disruption, pelvic ring fractures with direct bone bleeding, pelvic venous plexus tears, etc.
Clinical and epidemiological studies have indicated gender differences in the response to various adverse circulatory conditions (Offner 1999). In this regard, studies have shown that sex steroids have either deleterious or beneficial effects on cardiac and hepatic functions not only under normal conditions but also after circulatory stress. For example, testosterone-receptor blockade after trauma-hemorrhage has been shown to improve organ functions in males (Remmers 1998). Alternatively, castration days before hemorrhagic shock prevented the depression in myocardial functions that is usually observed in males under those conditions (Remmers 1997). Furthermore, significantly reduced cardiovascular morbidity and mortality has been reported in post-menopausal women receiving hormone replacement therapy (Stampfer 1991). Moreover, studies have indicated that 17β-estradiol is involved in various physiologic processes such as vascular response modulation.
It has been demonstrated that the proestrus state of the female rodent shows the highest plasma concentration of estradiol and prolactin (Smith 1975). The plasma levels of both hormones are low on the morning of estrus and then gradually increase over diestrus to achieve their peak levels on the morning of proestrus (Smith 1975). Studies by Slimmer and Blair (Slimmer 1996) have shown that female rats in the proestrus stage of the reproductive cycle exhibit a more vigorous restitution response than either estrus females or males after simple hemorrhage.
Furthermore, Wichmann et al. (1996) have shown that female mice subjected to hemorrhage during the proestrus state have enhanced immune responses as opposed to decreased responses in males. Therefore, the female reproductive cycle is an important variable not only with regard to immunological responses but also by influencing physiological responses (i.e., cardiac and hepatic functions) after trauma-hemorrhage and resuscitation (Angele 1999).
Trauma-hemorrhage produces a pronounced depression of immune functions in males that persists for up to 10 days after resuscitation (Chaudry 1992; Xu 1998). Alterations in the function of various macrophage (MΦ) populations (peritoneal, splenic, hepatic [Kupffer cells]) has been implicated in the immune depression and subsequent increased susceptibility to sepsis observed under such conditions (Ayala 1989; Ayala 1990; Ayala 1991). It has been shown that testosterone plays a significant role in producing this immunodepression and increased susceptibility to subsequent sepsis after trauma-hemorrhage. (Wichmann 1997; Angele 1997; Wichmann 1997). In contrast, female mice in the proestrus state of the estrus cycle have maintained or enhanced immune responses under such conditions; this is associated with improved survival after the induction of subsequent sepsis. (Diodato 2000; Slimmer 1996). What is needed in the art are methods and compositions related to treating trauma-hemorrhage comprising administering estrogen to a subject in need thereof.